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Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Primary Purpose

Polycystic Ovary Syndrome, Hyperandrogenism

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Metformin

Progesterone

estrace

About this trial

This is an interventional basic science trial for Polycystic Ovary Syndrome focused on measuring hyperandrogenemia

Eligibility Criteria

10 Years - 17 Years (Child)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Girls ages 10 to 17
Hyperandrogenemic (free testosterone greater than 2.5 standard deviations above the mean for normal control subjects of the same Tanner Stage)
Creatinine clearance > 90 ml/min as calculated by the Cockcroft-Gault equation
Hemoglobin > 12 mg/dL or Hematocrit > 36%
Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
Sexually active subjects must agree to abstain or use double barrier contraception during the study
Subjects must agree not to take any other medications during the course of the study without approval by the study investigators.

Exclusion Criteria:

Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation
Hemoglobin <12 mg/dL or hematocrit < 36%
Abnormal liver function tests, including Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin, Albumin, and Alkaline Phosphatase
Weight < 34 kg
History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer
Pregnant or breast feeding
On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone)
Are currently participating in another study or have been in one in the last 30 days.
Subjects using restricted medication (see restrictions below) are excluded unless the subject's primary care provider approves stopping the medication.

Sites / Locations

Center for Research in Reproduction, University of Virginia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Metformin, progesterone , estrace

Arm Description

12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X)

Outcomes

Primary Outcome Measures

Change in Progesterone Sensitivity Index Before and After Metformin Treatment.

The progesterone (P4) sensitivity index is defined as the percent change in 11-hour LH pulse frequency before and after P4 and estradiol administration for 7 days, divided by the day 7 mean serum P4 concentration. We compared the P4 sensitivity index after metformin administration to the baseline P4 sensitivity index, using Wilcoxon signed-rank test.

Secondary Outcome Measures

Full Information

NCT ID

NCT01427595

First Posted

August 30, 2011

Last Updated

December 14, 2020

Sponsor

University of Virginia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT01427595

Brief Title

Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

Official Title

Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone in Hyperandrogenemic Adolescent Girls (JCM025)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2020

Overall Recruitment Status

Completed

Study Start Date

February 18, 2009 (Actual)

Primary Completion Date

January 17, 2015 (Actual)

Study Completion Date

January 17, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Virginia

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Many, but not all, girls with high levels of the male hormone testosterone go on to develop polycystic ovary syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual periods, excess facial and body hair, and weight gain. PCOS is also a leading cause of difficulty becoming pregnant. The investigators do not understand why some girls with high hormones develop PCOS and others do not. In a previous study by our group, some girls with high levels of male hormones had abnormalities in the secretion of another hormone, called luteinizing hormone (LH), that are often seen in women with PCOS. However, another group had normal LH secretion. The girls with the abnormal LH secretion had higher levels of another hormone, called insulin, than the girls with normal LH secretion. The investigators will test whether metformin, an insulin-sensitizing agent, changes the effects of high male hormone levels in adolescent girls, specifically by looking at their LH secretion response following metformin treatment.

Detailed Description

A better understanding of the factors that make adolescent girls more or less susceptible to the adverse neuroendocrine effects of elevated androgens will hopefully lead to improved prevention and treatment strategies for PCOS. In this study, we propose to explore the role of hyperinsulinemia on neuroendocrine function in hyperandrogenic adolescent girls by assessing the effect of the insulin sensitizer Metformin on hypothalamic progesterone sensitivity. Other differences between the progesterone sensitive and progesterone insensitive subgroups, including racial and ethnic differences between the two populations and a trend towards older gynecologic age in the progesterone insensitive population, are being pursued through other ongoing studies (IRB-HSR# 8588 and 12160).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome, Hyperandrogenism

Keywords

hyperandrogenemia

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Metformin, progesterone , estrace

Arm Type

Experimental

Arm Description

12 weeks Metformin oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (2X) oral estrace, 0.5-1 mg once a day for seven days (2X)

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

500-2000 mg PO BID (X12 weeks)

Intervention Type

Drug

Intervention Name(s)

Progesterone

Intervention Description

oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500, and 2300 hr for seven days (X2)

Intervention Type

Drug

Intervention Name(s)

estrace

Other Intervention Name(s)

Estrogen

Intervention Description

oral estrogen (estrace, 0.5-1 mg once a day for seven days)- X2

Primary Outcome Measure Information:

Title

Change in Progesterone Sensitivity Index Before and After Metformin Treatment.

Description

Time Frame

12 weeks following start of metformin treatment

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

10 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Girls ages 10 to 17 Hyperandrogenemic (free testosterone greater than 2.5 standard deviations above the mean for normal control subjects of the same Tanner Stage) Creatinine clearance > 90 ml/min as calculated by the Cockcroft-Gault equation Hemoglobin > 12 mg/dL or Hematocrit > 36% Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia) Sexually active subjects must agree to abstain or use double barrier contraception during the study Subjects must agree not to take any other medications during the course of the study without approval by the study investigators. Exclusion Criteria: Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia) Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation Hemoglobin <12 mg/dL or hematocrit < 36% Abnormal liver function tests, including Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin, Albumin, and Alkaline Phosphatase Weight < 34 kg History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer Pregnant or breast feeding On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone) Are currently participating in another study or have been in one in the last 30 days. Subjects using restricted medication (see restrictions below) are excluded unless the subject's primary care provider approves stopping the medication.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John C. Marshall, MD, PhD

Organizational Affiliation

University of Virginia

Official's Role

Principal Investigator

Facility Information:

Facility Name

Center for Research in Reproduction, University of Virginia

City

Charlottesville

State/Province

Virginia

ZIP/Postal Code

22908

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

29095983

Citation

Lundgren JA, Kim SH, Burt Solorzano CM, McCartney CR, Marshall JC. Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin. J Clin Endocrinol Metab. 2018 Jan 1;103(1):263-270. doi: 10.1210/jc.2017-02068.

Results Reference

derived

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Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

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